This application from a new independent investigator seeks support for a study that addresses an important problem in geriatric psychopharmacology. Schizophrenia is a life-long illness requiring daily treatment with antipsychotic medication. In contrast to antipsychotic dosing in younger patients, the minimal therapeutic dose in older patients remains unknown. Clinical guidelines based primarily on expert consensus have recommended the use of lower antipsychotic doses in older patients with schizophrenia, and dose reduction has been advocated for patients stable on higher doses. However these guidelines are based on limited empirical data that do not take into account mechanistic processes involved in drug sensitivity associated with aging. Previous Positron Emission Tomography (PET) studies in young and mid-life patients with schizophrenia have established a therapeutic window of antipsychotic drug occupancy at striatal dopamine D2/3 receptors which has been successfully employed in predicting the clinically effective doses for new and established antipsychotic drugs in younger patients. Towards the goal of establishing the lowest effective maintenance dose of antipsychotic medication in older patients with early-onset schizophrenia, we propose a PET study using a prospective within-subject design. We will determine an estimate of risperidone D2/3 occupancy associated with maintenance of response in 40 patients 60 years and older with onset of schizophrenia before the age of 45 years and maintained on a single antipsychotic (risperidone) at a steady high dose of >3.5 mg per day for at least one year. They will undergo a gradual dose reduction up to 40% of their baseline dose to a target dose not lower than the recommended dose range of 1.25 - 3.5 mg/day. A [11C]raclopride PET scan will be completed at baseline and after dose reduction. They will then be followed for 6 months to determine clinical outcome. If they show signs of clinical deterioration, they will have their dose titrated up until clinical response is restored, and then undergo a third PET scan to establish the drug binding at the clinically effective dose. The results of this study will be used in future studies incorporating population pharmacokinetic methodology, translating the drug occupancy data collected in this to individualized dosing of risperidone for older patients with schizophrenia. This can be achieved in clinical practice using little more than standard laboratory assays to determine the lowest effective antipsychotic dose necessary for maintenance of therapeutic effect in older patients with schizophrenia, a clinical question of major public health significance. PUBLIC HEALTH RELEVANCE: Schizophrenia is a life-long condition that requires long-term treatment with antipsychotic medications to prevent relapse of psychotic symptoms. As patients with schizophrenia become older, they become more sensitive to medication side effects and require a reduction of antipsychotic dose. However, since the minimal effective dose of antipsychotic medications in older patients is not known, most of them are treated with doses that are too high. Studying the extent of antipsychotic drug binding to brain receptors using positron emission tomography (PET) will allow for the prediction of the lowest effective dose required to maintain wellness in older patients.